1. FIELD OF THE INVENTION
The present invention relates to certain novel piperazine derivatives having protracted uro-selective xcex11-adrenoceptor antagonistic activity exceeding those of previously described compounds. The compounds of the present invention hold promise for treating benign prostatic hyperplasia (BPH). This invention also relates to methods for making the novel compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hyperplasia using the compounds.
2. DESCRIPTION OF THE RELATED ART
A review in J.Med.Chem. 1997, V.40, No.9, pp.1292-1315, describes the most important pharmacological options available at present in the treatment of benign prostatic hyperplasia. The two most successful therapies are based on xcex1-adrenergic receptor antagonism and androgen levels modulation by 5xcex1-reductase inhibitors. 5xcex1-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. xcex11-antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore the preferred modalities of treatment in the control of benign prostrate hypertrophy. xcex11-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus, xcex11-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
The more important of the xcex11-adrenoceptor antagonists which are currently used in the management of BPH are shown below. 
However, most of these known drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headaches, etc.) due to lack of selectivity of action between prostatic and vascular xcex11-adrenoceptors. Clearly, xcex11-adrenoceptor antagonists which have inherently greater selectivity for prostatic xcex11-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective xcex11-adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
Recently, it has been demonstrated that the prostate tissue of higher species like man and dog is overvalued by low affinity xcex11A-adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel xcex11-antagonists, namely, a new class of piperazine if compounds, with greater selectivity of action against xcex11A-adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.
There are many descriptions in the literature of the pharmacological activities associated with penyl piperazines. Eur. J. Med, Chem. -Chimica Therapeuetica, 1977, V. 12, No. 2, pp. 173-176, describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below as anorectic agents with no CNS side effects. 
The synthesis and pharmacology of some 2-[3-4aryi-1-piperazinyl)propyl]-1H-benz[de]isoquinolin- 1,3(2H)-diones/2,5-pynolidinediones (J. Indian Chem. Soc., 1986, V. LXIII, pp. 529-530), of N4-aryl-N1-piperozinyhnethyl)4-(4xe2x80x2-methoxyphenyl)piperidine-2,6-diones(J. Indian Chem. Soc., 1978, v. LV, pp.819-821), and of N(N4-arylpiperazinylalkyl)- phthalimides (J. Indi an Chem. Soc., 1979, V. LVI, pp. 1002-1005), as shown below, have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals. 
However, in those papers there is no mention of the adrenoceptor blocking activity of these compounds, and thus their usefulness in the treatment of benign prostate hyperplasia did not arise.
The earlier synthesis of various 1-(4-aryl-piperazine-1-yl)-3-(2-oxo-pyrrolidin-1-yl/piperidin-1-yl) alkanes and their usefulness as hypotensive and antisehemic agents is disclosed in unpublished Indian patent applications DEL 496/95 (Mar. 3, 1995), DEL500/95 (Mar. 21, 1995) and DEL/96/96 (Mar. 29, 1996) by the inventors herein. These compounds had low xcex11-adrenergic blocking activity (pKixcx9c6 as compared to  greater than 8 of the known xcex11-antagonists such as prazosin), and practically no adrenoceptor subclass selectivity for xcex11A vs xcex11B or 60 1D adrenoceptors. It has now been discovered that structural modification of these compounds from lactam to dioxo compounds, i.e., from 2-oxopyrrolidin to 2,5- dioxopyrrolidin and 2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for xcex11A in comparison to xcex11B-adrenoceptor blocking activity, an essential requirement A for compounds to be good candidates for treatment of BPH.
An object of the present invention, therefore, is to provide novel arylpiperazine derivatives that exhibit significantly greater xcex11A-adrenergic blocking potency the available with the known compounds in order to provide specific treatment for benign prostatic hyperplasia.
It is also an object of the invention to provide a method for synthesis of the novel compounds.
It is a further object of the invention to provide compositions containing the novel compounds which are useful in the treatment of benign prostatic hyperplasia.
The above-mentioned objectives are achieved by a novel class of piperazine derivatives of general Formula I below 
wherein Y is O or S; Q, X, Z and Zxe2x80x2 are independently CH or N; m=0-3; n=0-4; R1, R2 are independently selected from: H, F, Cl, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3 is H, R6, OH or OR6; R6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R4, R5 are H, C1-3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring. Preferably, R1 is H, R2 is H, Cl or CF3, R3, R4, and R5=H Y=O and Q=CH when m=0 and n=1; or R1 is H, R2 is OCH3, R3, R4 and R5=H, Y=O and Q=CH when m=0 and n=2.
Compounds within the scope of Formula I but having the structure of Formula II below 
wherein n, X, Z, Zxe2x80x3 Rxe2x80x21, R2 and R3 are as defined for Formula I, and wherein mxe2x80x2=1-4, are preferred as selective and potent xcex11A-adrenoceptor antagonistic activity over the xcex11B- and xcex11D-adrenoceptors. In Formula II, preferably R1 is H, R2 is H, Cl or CF3, and R3 is H when mxe2x80x2=1 and n=1; or R1 is H, R2 is OCH3, and R3 is H when mxe2x80x2=1 and n=2.
The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia These compositions comprise an effective amount of at least one of the above compounds of Formula I, or preferably of Formula II, and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier.
An illustrative list of particular compounds of the invention is given below:
Compound Chemical Name
No.
1. 1-[4-(4-Fluorophenyl)piperazine-1-yl]-3-(2,5-dixopyrrolidin-1-yl)propane
2. 1-[4-(2-Methox phenyl)piper azin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
3. 1-[4-(3-Trifluoromethylphenyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
4. 1-[4-(2-Pyridyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
5. 1-[4(3-Chlorophenyl)piperazine-1-yl]-3-(2,5dioxopyrrolidin-1-yl)propane
6. 1-[4(2-Pyrimidyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
7. 1-[4(3,4-Dimethylphenyl)piperazine-1-yl]-3-(2,5-dioxopyrrolidin- 1-yl)propane
8. 1-[4-(Phenylpiperazin)-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
9. 1-[4-(2-Metboxyphenyl)piperazine-1-yl]-4(2,5-dioxopyrrolidin-1-yl)butane
10. 1-[1-4(2-Metboxyphenyl)piperazine-1-yl]-2(2,5diosopyrrolidin-1-yl)ethane
11. 1-[4-(3-Methoxyphenyl)piperazine-1-yl]-3(2,5-dioxopyrrolidin-1-yl)propane
12. 1-[4(4-Methoxyphenyl)piperazine-1-yl]-3(2,5dioxopyrrolidin-1-ylopropane
13. 1-[4-(2-Methoxyphenyl)piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
14. 1-[4(4-Fluorophenyl)piperann-1yl]-3-(2,6-dioxopiperidin-1-yl)propane
15. 1-[4-(4-Chlorophenyl)piperazine-1-yl]-3-(2,6-dioxopiperidia-1-yl)propant
16. 1-4-(3-Trifluoromethylphenyl)piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
17. 1-[4-(2-Fluorophenyl)piperazine-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
18. 1-[4-(2-Methylphenyl)piperazine-1-yl]-3-(2,6dioxopiperidin-1-yl)propane
19. 1-[4-(2-Pyridyl)piperazine-1-yl)-3-(2,6-dioxpiperidin-1-yl)propane
20. 1-[4-(3-Chlorophenyl)piperazine -1-yl]-3(2,6-dioxopiperidin-1-yl)propane
21. 1-[4(3,4-Dimethylphenyl)piper -1-yl]-3(2,6-dioxopiperidin-1-yl)propane
22. 1-[4(2-Pyrimidyi)piperazine-1-yl]-3-(2,6diozopiperidin-1-yl)propane
23. 1-[4-(3-Methoxyphenyl)piperazine-1-yl]-3-(2,6dioxopiperidia-1-yl)propane
24. 1-[4(4-Methoxyphenyl)piperazine-1-yl]-3-(2,6dioxopiperidin-1-yl)propine
25. 1-[4-(2-Methoxyphenyl)piperazine-1-yl]-(2,6-dioxpiperidin-1-yl)butane
26. 1-[4-(2-Methoxyphenyl)piperazine-1-yl]-3-[2-ioxo-3-phenyt-pyrolidin -1-yl]propane
27. 1-[4-(Phenyo)piperidin-1-yl]-3-2,5-dioxopyrolidin-1-yl]propane